Acylated s-triazines and process for their preparation



Jan. 21, 1964 P. GIRALDI ETAL ACYLATED S-TRIAZINES AND PROCESS FOR THEIRPREPARATION 2 Sheets-Sheet l Filed Dee.

Compound I o 0 Control: 0- ---0 Treaad (dose I40mg/kg/day) 7 6 5 4 3 2mE2u E 32. 3.2. 3 33.6...

6 8 10 I2 I4 I6 I8 20 22 24 26 28 day;

FIG. I

0 2 4 6 810l2|4|6|8 20 222426 28days FIG.2

ATTORNEYS United States Patent 3,118,888 ACYLATED s-TRIAZINES AND PRCESSFOR THIEER PREPARATIGN Pie1nicoa Girai, Demenim Artini, Giixmio Nannini,ami Wiiy Logemann, Miiafi, Eay, assiguors m Carlo Erba S.p.A., Milan,Italy, a cerperation of EtaEy Filed Dec. 17, 1962, S92. No. 245,226Clams prioriy, application Iay Dec. 22, 1961 4 Claims. (Cl. 260-2 399)We have found that some types of triazines (Italian patent appln. No.5,179/ 60) show an antiviral activity in the B type Lee and Crawinfluenza strains on mice.

We have now ascertained that products of the following formula H-C C-N-RH Il N whore R which are more toxic than compounds containing di-3,118,883 Patente Jan. 21, 1964 phenyl-ether or diphenyl-thioether, thebis-acetylation is not suficient for reducing the toxicity to levelssupportable for the clinical use.

These products are synthesized by acylation of the product illustratedin the general formula; e.g. treatment of acetic anhydride with solventsresults in a mono-acetylderivative; a diacetyl product is obtainedresorting che acetic anhydride only; if different anhydrides are used,mixed acylated products are obtained.

The first acylic residue links on the hydrogen of the amino-group inposition 4.

The second acylic residue links on the nitrogen in position 2. Thefollowing FIGURES (I, 2, 3 and 4) show the toxicity differences existingbetween the two Products (I, 11) of the following formulae:

The Tables 1 and 2 show the antiviral activity in the B type Lee andCraw influenza strains of the Product (11) at diflerent infecting doses.The antiviral activity was established by the mortality differencesbetween two groups of mice treated or not treated (each group wascomposed of 15 animals) and by the differences of lungs weight betweenthe same groups of animals.

The mica were infected with decreasing doses of the two strains of virus(ElD=egg infecting dose).

The administration of the product in animals was started 24 hours beforeinjection.

TABLE 1 Activz'ty o) Compound II in Mice Infeczed Wth T ype B CrawInfluenza Strains (2 Mg. Per Day by Oral Route in 2 Doses) 'Iyps Bstrai.n Type B stran Type B strain Type B stran Craw 10 EID Craw 10 EIDCraw 10 EID Oraw 10 EID mortality rate mortality rate mortulity ratemortalty rate Treated Controls Treated Controls Treated Controls TreatedControls Average lungs weight:

'Iteated animals, g... Control anmals, g

= Start of treatment. b Infection of animals.

TABLE 2 Activity Compozmd II in Mica lnfected With T ype B Lee InfluenzaStrains (2 Mg. Per Day by Ora! Route in 2 Doses) Type 13 strain Lee 10EID mortality rate Type B strain Leo EID mortality rate 'Iype B stranLee 10 EID mortality rate Type B strain Leo 10 EID mortality rateTreatcd Controls Trcatcd Controls Trcated Contro1s Trcated Controls Timein dnys:

Avemgo 1ungs weight:

Trcated nnimnls, g... Contro] aninmls, g..-

Start of treetment. b Infection 01 animals.

This invention is illustrated but not lmited by the fol- 0 lowingexamples.

61 g. o-phenoxy-phenyl-biguanide hydrochloride and 14 g. H.COO.Na arerefluxed for 5 h. in 250 ml. H.COOH, then cooled and alkalized with 20%NaOH. Crystallization from 95% alcohol results in 2-(N-o-phenoxy-phenyl)amino-4-amino-1,3,5-triazine (M.P. 175-176 C.).

15 g. 2-(N-o-phenoxy-phenyl)amino-4-amino-l,3,S-trig. (I) dissolved in250 ml. anhydrous dioxane are added with 10 g. triethyl-arnine, 6 g.acetic acid, 5 g. palladium on charcoal and reduced to resulting in2-{N- EXAMILE 1 azine and 11.1 ml. acetc anhydride are refiuxed for 6 40hours in 150 ml. benzene, then evaporated to dryness in vacuum. Theresidue is washed with ether. tion from isopropyl-alcohol results in2-(N-o-phenoxyphenyl)amino-4-(N-acetyl)-amino-l,3,5 triazine (M.P.173-175" C.).

16.8 g. 2-(N-o-phenoxy-phenyl)-arnino-4-amino-L3,S- trazine are refiuxedfor 6 hours in 30 ml. acetic anhydride, then cooled to +10 C.; thesolution is treated with water, then filtered. The precipitate is washedwith ether and crystallized from isopropyl-alcohol to obtain 50 fluxedfor 10 hours in 80 ml. benzene, then evaporated2-(N-o-phenoxy-phenyl-N-acetyl)amino 4 (N-acetyl)- amino-1,3,S-triazine(M.P. 165-167 C.).

Crystallizao-[ (p-carboxy-methyl-phenoxy) -phenyl] }-amino-4-amino-1,3,5-triazine (II) (M.P. 135 C.).

10 g. (11) are dissolved in 30 ml. acetc anhydride added with 4 g.melted sodium acetate and refluxed for 6 hours, then poured on ice.Crystallization from 95% ethanol results in a product corresponding todiacetate (M.P. 178-180 C.).

EXAMPLE 4 8.1 g. 2-(N-o-phenoxy-phenyl)amino-4-amino-l,3,S-trazine and26.3 g. benzoic anhydride are refluxed for 10 hours in 160 ml. benzene,then evaporated to dryness in 5 vacuurn. Crystallization of the residuefrom acetone rer) EXAI\IPLE I 11.3 g. p-diphenylsulphide-biguanidehydrochloride and 2.2 g. H.COO.Na are refluxed for 5 hours in 75 ml.H.COOH, then cooled, alkalized with 20% NaOI-I. Crystallizaton fromdiluted alcohol results in2-(N-p-diphenylsulphide)amino-4-amino-l,3,5-triazine (M.P. 203-204" C.).

5 g. 2-(N-p-diphenylsulphide) amino 4 (N acetyl) amino-1,3,S-triazineare refluxed for 10 hours in 20 ml. acetic anhydride, then cooled,poured in water. Crystallization from diluted doxane results in2-(N-p-dipheny1- sulphldcN'acetyl)'ammo'4'(Nacetyl)ammo is cooled,poured into water, and the precipitata is crysazine tallized fromdiluted dioxane to obtain 2-(N-p-phenoxy- 10 g.o-[(p-carboxymethyl-phenoxy)-phenyl]-amine dis- 15 g. solved in 50 m1.ethyl-acohol are refluxed with 6.8 g. aminodichloro-s-triazine and 2 g.sodium carbonate for 5 hours, then coo1ed and filtered. Crystallizationof the precipitate from methanol results in2{N-o-[(p-carboxymethyl-phenoxy)-phenyl]}-amino-4-amino-6-chloro 1,3,5-triazine (I) (M.P. 185 C.).

sults in 2-(N-o-phenoxy-phenyl)-arnino-4-(N-benzoyl)amino-1,3,S-triazine (M.P. 180 C.).

4 g. 2-(N-o-phenoxy-phenyl) amino 4 (N benzoyl) amino-1,3,5-triazine and5.7 1111. acetc anhydride are reto dryness in vacuum. Crystallization ofthe residue fr0m ethyl-alcohol results in2-(N-o-phenoxy-phenyl-N-acetyl) amno-4-(N-benzoyl)aminod,3,S-triazine(M.P. 175-176 EXAMILE 5 58 g. of p-phenoxy-phenyl-biguanide.HCl and 12.9g. of HCOONa are refluxed for 5 hours in 240 ml. of HCOOH. The mixtureis cooled, alkalized with 20% NaOH, and crystallized from dioxane toobtain 2-(N-p- 60 phenoxy-phenyl)amino-4-amino-1,3,5-triazine (M.P. 233-30 g. of 2-(N-p-phenoxy-phenyl)an1ino-4-aminol,3,5- triazine and 22 ml.of acetic anhydride are refluxed for 12 hours in 150 ml. of glacialacetic acid. The solution phenyl)amino-4-(N-acetyl)-amino-1,3,S triazine(M.P.

EXAMPLE 3 0 of 2- (N-p-phenoxy-phenyl) amino-4- (N-acetyl) 7amino-1,3,5-triazine are refluxed for 6 hours in 45 ml. of

acetic anhydride.

precipitate obtained is filtered, washed with ether and crystallizedfrom 99.9% ethanol to obtan 2-(N-p-phenoxy-phenyl-N-acetyl)amno-4-(N-acetyl) amino-1,3,S triazine (M.P. -151 C.).

The solution is cooled at +10", the

1.2-(N-O-PHENOXY-PHENYL-N-ACETY)AMINO-4-(N-ACETYL)-AMINO-1,3,5-TRIAZINE.